Journal Article

Mechanism of Polybrominated Diphenyl Ether Uptake into the Liver: PBDE Congeners Are Substrates of Human Hepatic OATP Transporters

Erik Pacyniak, Megan Roth, Bruno Hagenbuch and Grace L. Guo

in Toxicological Sciences

Volume 115, issue 2, pages 344-353
Published in print June 2010 | ISSN: 1096-6080
Published online February 2010 | e-ISSN: 1096-0929 | DOI:
Mechanism of Polybrominated Diphenyl Ether Uptake into the Liver: PBDE Congeners Are Substrates of Human Hepatic OATP Transporters

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Polybrominated diphenyl ethers (PBDEs) are flame-retardants that upon chronic exposure enter the liver where they are biotransformed to potentially toxic metabolites. The mechanism by which PBDEs enter the liver is not known. However, due to their large molecular weights (MWs ∼485 to 1000 Da), they cannot enter hepatocytes by simple diffusion. Organic anion–transporting polypeptides (OATPs) are responsible for hepatic uptake of a variety of amphipathic compounds of MWs larger than 350 Da. Therefore, in the present study, Chinese hamster ovary cell lines expressing OATP1B1, OATP1B3, and OATP2B1 were used to test the hypothesis that OATPs expressed in human hepatocytes would be responsible for the uptake of PBDE congeners 47, 99, and 153. The results demonstrated that PBDE congeners inhibited OATP1B1- and OATP1B3-mediated uptake of estradiol-17-β-glucuronide as well as OATP2B1-mediated uptake of estrone-3-sulfate in a concentration-dependent manner. Direct uptake studies confirmed that all three PBDE congeners are substrates for the three tested hepatic OATPs. Detailed kinetic analysis revealed that OATP1B1 transported 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) with the highest affinity (Km = 0.31μM) followed by 2,2′,4,4′,5-pentabromodiphenyl ether (BDE99) (Km = 0.91μM) and 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) (Km = 1.91μM). For OATP1B3, the order was the same (BDE47: Km = 0.41μM; BDE99: Km = 0.70μM; BDE153: Km = 1.66μM), while OATP2B1 transported all three congeners with similar affinities (BDE47: Km = 0.81μM; BDE99: Km = 0.87μM; BDE153: Km = 0.65μM). These results clearly suggest that uptake of PBDEs via these OATPs is a mechanism responsible for liver-specific accumulation of PBDEs.

Keywords: polybrominated diphenyl ethers; organic anion–transporting polypeptides; liver; uptake assay; kinetics

Journal Article.  4897 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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